wake of the STEP trial, PAVE 100, a planned efficacy trial of a vaccine with
similarities to the STEP vaccine, was slimmed down to a safety trial. At the
same time, Phambili, intended to be a companion trial to STEP using a vaccine
tailored to the southern African population, was stopped.
originally designed to include 8500 volunteers in the United States, South
America, the Caribbean and Eastern and Southern Africa. The study was to begin
US recruitment in October 2007 but was postponed following the decision to halt
immunisations in the STEP study.
PAVE was designed to study a
different vaccine product, called VRC, which consisted of a DNA-based
plasmid vaccine and a follow-up booster vaccine that used an adenovirus to
deliver recombinant HIV sequences from a variety of
was little scientific confidence that PAVE would lead on directly to licensing
of the VRC vaccine. Instead, the study would at best have provided further
information to the field about immune responses. An advisory group recommended
in May 2008 that a smaller version of PAVE 100 should go ahead, which would
measure if the vaccine reduced viral load in people who became infected despite
suggestion of such a reduction, at least in women, had been seen in the
Phambili trial, which was stopped in the wake of STEP.1
Phambili trial was a companion to the STEP trial, testing the Ad5 vaccine in
high-risk men and women in South Africa, and was intended as a test of the
vaccine’s potential for cross-clade protection. The Merck vaccine was based on
HIV-1 subtype B, but the dominant subtype of HIV circulating in South Africa is
was designed to recruit 3000 high-risk men and women at five sites across South
Africa, but was halted when the decision was reached to close the STEP study.
By this point the study had recruited 801 participants.
Gray reported interim results to December 2008 at the Paris AIDS Vaccine
conference in October 2009. At this point 90% of participants were still
undergoing follow-up; 80% of participants had received at least two
vaccinations before study vaccinations were halted.
Gray reported that women who became infected despite vaccination showed a trend
towards a lower viral load setpoint (nearly fourfold or 0.57 log, p=0.09) than
women who became infected in the placebo group. However, the numbers involved
were small, and the difference in viral load setpoints was not matched by a
sustained difference in CD4 cell counts. Overall, the viral load and CD4 trends
showed no significant difference, said Dr Gray, but the viral load setpoint
effect in women required further study.
annual infection rate was 4.69% in the vaccine group and 3.8% in the placebo
group, with a hazard ratio of 1.26 (95% confidence interval 0.76 to 2.10,
p=0.37). Although none of the differences in infections or infection rates
between the two arms were statistically significant, there were always more
infections in the vaccine arm, no matter how the data were compared.
Baltimore, President of the American Association for the Advancement of Science
(AAAS) and the discoverer of reverse transcriptase, made a pessimistic
assessment of the state of HIV vaccine research to the AAAS Conference in
February 2008. His remarks were taken up by the world’s press.2
the conference that the failure of every promising approach to an HIV vaccine
had led many scientists to wonder whether it would ever be possible to create
one. No research projects currently underway, including his own, had any
realistic prospect of producing a vaccine for at least a decade, and success
might take even longer, he said. “The community is depressed,” he admitted,
“because we see no hopeful route to success.”
such a sad topic,” he said of the search for an AIDS vaccine. “We have been
trying to make an HIV vaccine since the day HIV was discovered. In 1984, we
were told that as the virus had been found, a vaccine should be just around the
corner. History was on our side - we have been able to make vaccines versus
almost all the viruses that affect humans. But we are no closer to a vaccine
now than we were then.
“Every year since then, we have been saying it is at
least 10 years away. I still think it is at least 10 years away. And if it has
been 10 years away for 20 years, you might ask does that really mean it will
never happen? I’m not prepared to say that, because I don’t want to take a
pessimistic stand. This is too important to give up on. Our lack of success may
be understandable, but it is not acceptable.”